Roles Of Spatial Learning In Synaptic Plasticity And Neurogenesis In Alzheimer's Disease Models

[Background]Cognitive stimulation therapy can improve cognitive function and slow the hippocampal atrophy in patients with Alzheimer's disease (AD), however, the molecular mechanism remains unclear. Spatial training reduces β-amyloid (Aβ) deposition, tau neuropathology and improves learning in a transgenic mouse model of AD. Synaptic loss, synaptic plasticity deficits and impaired neurogenesis are strong correlates of cognitive impairment in AD transgenic mice and AD patients. The impacts of hippocampus-dependent spatial learning on the above AD lesions have not been reported.[Objective]To explore the roles of spatial training in synaptic plasticity and neurogenesis in several animal models of AD.[Methods]Three kinds of AD animal models were trained in classic water maze for6days and sacrificed on the next day. Immunohistochemistry, silver staining and western blot were used to detect Aβ deposition. For measurement of synaptic plasticity, Golgi staining was used to analyse dendritic morphology and spine density in hippocampal CA1and DG neurons, and perforant path to dentate gyrus (PP-DG) long-term potentiation (LTP) was recorded. To explore the survival and proliferation of newborn neurons, we injected Brdu7d before the training and1-4d during the training, respectively.[Results]We demonstrate that spatial learning reduces the Aβ deposition in both lateral ventricle injection of Aβ1-42model and Tg2576transgenic mice. Spatial training increased the complexity of dendritic arbors, spine density and synaptic protein in three kinds of AD models. The LTP of PP-DG pathway was enhanced in lateral ventricle injection of Aβ1-42 and hyperhomocysteinemia animal models. Finally, we show that spatial training promotes the survival and proliferation of newborn neurons in lateral ventricle injection of Aβ1-42model. However, the survival and proliferation of newborn neurons did not change in Tg2576transgenic mice.[Conclusions]Spatial learning could reduce Aβ deposition, improve synaptic morphology and functions, promote the survival of newborn neurons, and rescue cognitive function in AD models.